PROJECT SUMMARY Problem to be Solved: Lung cancer (LC) is the leading cause of cancer related deaths in the United States (U.S.) and worldwide. In 2012, a total of 1.8 million new cases were estimated globally, accounting for 12.9% of all new cancer diagnoses. Although significant improvements in disease management and treatment have emerged, the prognosis for the majority of LC patients remains poor due to innate and acquired resistance to therapy. LC is a significant burden to the U.S. healthcare system because of costs associated with patient care ($13.4 billion) and lost productivity due to premature death ($36.1 billion). There remains an unmet need for new therapies to compliment or replace existing treatments and improve outcomes for patients. Product and Long-term Goal: CYD-2-11 is a small molecule Bcl-2 associated X protein (Bax) activator being developed as an oral therapeutic that disrupts cancer progression by inhibiting phosphorylation of amino acid residue serine 184 (S184), and activating Bax pro-apoptotic function. This Phase I SBIR project aims to demonstrate the feasibility of oral doses of CYD-2-11 as a well tolerated and efficacious therapeutic in a mouse xenograft model of LC, and investigate dose response relationships. Technological Innovation: CYD-2-11 targets a binding pocket adjacent to S184 to inhibit phosphorylation and directly activate Bax induced apoptosis. Potent inhibitory activity was demonstrated in vitro against LC cell lines and in several mouse models of human LC when administered intraperitoneally. No signs of toxicity were observed in all studies, which is correlated with lower levels of Bax expression in healthy cells and tissues. Phase I Objectives: This Phase I SBIR project aims to demonstrate the feasibility of oral doses of CYD-2-11 as a safe and effective therapeutic in A549 LC xenografts and to also define a dose response relationship. Phase II studies will further invetigate ADME and toxicokinetic studies in preparation for an investigational new drug application with the FDA. Commercial Opportunity: The American Cancer Society projects that over 222,500 new instances of LC will be diagnosed in the USA during 2017 and greater than 99% are estimated to express wild-type Bax. While the patient population most susceptible to treatment is yet to be defined, it is expected that CYD-2-11 will find use as a single agent or in combination therapy against a large portion of these cancers. Preliminary models forecast that the peak potential revenue for CYD-2-11 can approach $4 billion annually.